Klinefelter syndrome (KS/XXY) is the most common chromosomal abnormality in humans (1:650 males) and represents an excellent model in which to study the interplay between genetic factors and reproductive hormones on neurodevelopment. Males with KS have increased rates of verbal cognitive impairments, executive dysfunction, psychosocial problems, and motor skills deficits. Testosterone deficiency develops during adolescence in the majority of affected males, but objective data about the psychological and motor effects of testosterone replacement therapy in KS is lacking. Here we propose the first-ever placebo- controlled study of the psychological and motor effects of testosterone therapy in adolescents with KS. We hypothesize that testosterone therapy initiated in early puberty in KS/XXY will lead to improvements in executive function, psychosocial functioning, and motor skills, while externalizing behaviors will remain unchanged. We also hypothesize that genetic polymorphisms in the androgen receptor gene influence response to testosterone therapy. In the proposed research project we aim to: (1) study the psychological and motor effects of testosterone therapy in early adolescent males with KS/XXY and (2) investigate genetic factors influencing the clinical phenotype and response to testosterone therapy in KS/XXY, including androgen-receptor (AR) polymorphisms and parent-of-origin of the extra X chromosome. Our preliminary studies suggest that testosterone therapy started in early adolescence improves attention and self-report of personal adjustment, and does not lead to increased negative behaviors, and that individuals with the short CAG-repeat polymorphism of the androgen receptor gene have an improved response to testosterone therapy compared to the long CAG polymorphism. To accomplish our aims, we will conduct a randomized, prospective, double- blind, placebo-controlled trial of testosterone replacement therapy in Tanner 2-3 males with KS/XXY, comparing psychological factors (executive function, attention/inhibition, verbal fluency), behavior (social adjustment, aggression) and motor skills (strength, coordination) in testosterone versus placebo after 6 and 12 months of therapy. We will also evaluate if polymorphisms in the AR gene and the parent-of-origin of the extra X chromosome are related to the clinical phenotype or response to testosterone treatment. Results will influence treatment guidelines for testosterone in patients with KS/XXY and will lead to improved understanding of the pathophysiology of KS. As a subspecialist in Developmental-Behavioral Pediatrics, I am committed to becoming an independent investigator with a research program focused on understanding the role of hormonal and genetic factors on neurodevelopment and behavior in children with sex chromosomal disorders and other neurogenetic syndromes, and in conducting clinical trials to develop evidence-based treatments to improve medical and psychological outcomes of children. This application outlines five primary career development aims that will (1) lead to specialization in clinical trials design and execution for neurogenetic disorders, (2,3) enhance experience in neuropsychology and molecular diagnostic methods to enhance future research endeavors, (4) increase understanding of current neuroimaging and animal research on reproductive hormone effects on neurodevelopment, and (5) enhance abilities to design research in vulnerable populations of children with neurodevelopmental and neurogenetic disorders applying current bioethical principles. These aims will be reached through direct experience during the research project, mentoring sessions, personalized tutorials, and participation in related research discussion groups and research conferences. Supplementary didactic coursework in neuropsychology, behavioral genetics, neuroendocrinology, and biostatistics will also lead to a Masters degree in Clinical Science. This research project will recruit subjects through a unique clinic called the eXtraordinarY Kids Clinic, and will take advantage of strong infrastructure for research and career development support at The Children's Hospital and the UC-Denver Colorado Clinical &Translational Research Institute. I have a assembled a strong team of mentors and collaborators with broad and successful research careers in psychology, outcomes in sex chromosomal abnormalities, endocrinology, clinical trials, genotype-phenotype studies, neurogenetic syndromes, developmental disabilities, bioethics, and molecular biology. My institution has committed to providing protected time for research, additional research supports including research space, research pharmacy services, statistical and database support, bioethical consultation, tuition/fees for coursework, and any additional supports needed to successfully complete the research project and to enhance my career development into an independent investigator. PUBLIC HEALTH RELEVANCE: Klinefelter syndrome (47,XXY) affects over 230,000 males in the United States, and the hypogonadism (testosterone deficiency) associated with this syndrome leads to health problems and may also increase morbidity by negatively impacting psychological functioning, attention, behavior, and motor skills. This study will determine if there are psychological and/or motor benefits to earlier initiation of treatment in adolescents with XXY/Klinefelter syndrome, which would impact clinical care guidelines in this common genetic disorder. Understanding the genetic factors of the X chromosome related to the characteristics seen in males with XXY/Klinefelter syndrome is important to target neural pathways and to develop interventions.